PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells
PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells
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DOI：
10.4161/cbt.28553
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发表时间：
2014-06-01
影响因子：
3.6
通讯作者：
Dent, Paul
中科院分区：
文献类型：
--
作者：
Roberts, Jane L.;Booth, Laurence;Dent, Paul
我们确定了临床相关的磷酸二酯酶5（PDE 5）抑制剂是否与临床相关的化疗药物相互作用，以杀死髓母细胞瘤细胞。在髓母细胞瘤细胞中，PDE 5抑制剂与长春新碱/依托泊苷/顺铂以大于相加的方式相互作用，导致细胞死亡。PDE 5表达的敲低概括了PDE 5抑制剂药物与化疗药物的联合作用。显性阴性半胱天冬酶9的表达没有显著抑制化疗致死率，但与PDE 5抑制剂西地那非联合使用时确实显著降低了增强的杀伤作用。BCL-XL和c-FLIP-s的过表达抑制了单独和联合药物毒性。CD 95或FADD的敲低抑制药物组合毒性。用PDE 5抑制剂和化疗药物治疗促进自噬，其在治疗后12小时达到最大，并且以细胞类型依赖性方式敲除Beclin 1或ATG 5抑制或增强药物组合致死率。PDE 5抑制剂以一氧化氮合酶依赖的方式增强化疗诱导的DNA损伤的诱导。总之，我们的数据表明，PDE 5抑制剂与标准化疗药物联合治疗髓母细胞瘤代表了未来治疗这种疾病的一种可能的新方法。
We determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill medulloblastoma cells. In medulloblastoma cells PDE5 inhibitors interacted in a greater than additive fashion with vincristine/etoposide/cisplatin to cause cell death. Knockdown of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of dominant negative caspase 9 did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with the PDE5 inhibitor sildenafil. Overexpression of BCL-XL and c-FLIP-s suppressed individual and combination drug toxicities. Knockdown of CD95 or FADD suppressed drug combination toxicity. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy which was maximal at similar to 12 h post-treatment, and in a cell type-dependent manner knockdown of Beclin1 or ATG5 either suppressed or enhanced drug combination lethality. PDE5 inhibitors enhanced the induction of chemotherapy-induced DNA damage in a nitric oxide synthase-dependent fashion. In conclusion, our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for medulloblastoma represents a possible novel modality for future treatment of this disease.